Clonal hematopoiesis involving DNA damage response genes in patients undergoing lung transplantation is increased

by Selleckchem | Mar 23 2023

Background: Cellular stressors influence the development of clonal hematopoiesis (CH). We hypothesized that aging, environmental, inflammatory, and genotoxic stresses drive the emergence of CH in patients with severe lung disease undergoing lung transplantation.

Methods: We performed a cross-sectional cohort study of 85 patients with severe lung disease undergoing transplantation to characterize CH prevalence. We evaluated somatic variants using duplex error-corrected sequencing and germline variants using whole exome sequencing. We evaluated CH frequency and burden using chi-square and Poisson regression, associations with clinical and demographic variables using logistic regression, and associations with clinical outcomes using chi-square, logistic, and Cox regression.

Results: CH in DNA damage response (DDR) genes TP53, PPM1D, and ATM was observed at high frequency in transplant recipients compared to a control group of older adults [28% vs. 0%, aOR 12.9 (1.7-100.3), p=0.0002]. Age [OR 1.13 (1.03-1.25), p=0.014] and smoking history [OR 4.25 (1.02-17.82), p=0.048] were associated with CH in DDR genes. Germline variants causing predisposition to idiopathic pulmonary fibrosis, including telomere biology disorders and surfactant-related lung disease were identified but not associated with CH. DDR CH was associated with increased cytomegalovirus viremia compared to patients with no CH [OR 7.23 (1.95-26.8), p=0.009]] or non-DDR CH [OR 7.64 (1.77-32.89, p=0.012)], decreased lymphopenia (aHR 0.49 (0.27 - 0.90), p=0.021) and mycophenolate discontinuation [aOR 3.8 (1.3-12.9), p=0.031].

Conclusion: In patients with severe lung disease requiring lung transplantation, CH due to somatic variants in PPM1D, TP53 or ATM is highly prevalent and associated with post-transplant outcomes including cytomegalovirus activation and mycophenolate intolerance.

Comments：

In this study, the authors investigated the prevalence and clinical significance of clonal hematopoiesis (CH) in patients with severe lung disease undergoing lung transplantation. The authors used duplex error-corrected sequencing to evaluate somatic variants and whole exome sequencing to evaluate germline variants in a cohort of 85 patients undergoing transplantation. The authors found that CH in DNA damage response (DDR) genes TP53, PPM1D, and ATM was observed at a high frequency in transplant recipients compared to a control group of older adults. Age and smoking history were associated with CH in DDR genes, but germline variants causing predisposition to idiopathic pulmonary fibrosis were not associated with CH.

The authors also found that DDR CH was associated with increased cytomegalovirus viremia, decreased lymphopenia, and mycophenolate discontinuation. These findings suggest that CH due to somatic variants in PPM1D, TP53 or ATM is highly prevalent in patients with severe lung disease undergoing lung transplantation and may be associated with post-transplant outcomes including cytomegalovirus activation and mycophenolate intolerance.

It is important to note that this is a cross-sectional cohort study, and the associations found in this study do not necessarily indicate causality. Further studies are needed to investigate the mechanisms underlying the observed associations and to determine the clinical significance of CH in patients undergoing lung transplantation.